PSP205, a Novel Phenyl Sulfonyl Piperidine, Induces Apoptotic Cell Death in Colon Cancer by Modulating Coat Protein Complex-Mediated Vesicle Trafficking

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(4), P. 1072 - 1086

Published: Jan. 9, 2025

The endoplasmic reticulum (ER) stress and autophagic pathways offer attractive targets for the development of new cancer drugs. Here, we identified a novel phenyl sulfonyl piperidine, PSP205, that induces prolonged ER-stress-mediated autophagy apoptosis in colon cells. Transcriptome analysis cells exposed to PSP205 unveiled transcriptional upregulation genes associated with ER response or unfolded protein (UPR), addition vesicle transport. Among top upregulated genes, DNAJB9, XBP1, PDIA4, HSPA5, SEC24D, SEC11C are implicated stress. Gene set enrichment revealed gene sets involved UPR, mTORC1 signaling, hypoxia, P53 pathway, apoptosis, ER-Golgi-vesicle-mediated transport pathway. Mechanistic studies showed acts on IRE1-TRAF2-JNK pathway modulate flux, leading macroautophagy, ER-phagy, deformation Golgi. Our study also demonstrated decreases expression COPI coat complex subunit beta 2 (COPB2) presence COPB2 siRNA. Furthermore, synergistically killed combination proteasome topoisomerase inhibitors. Cumulatively, our findings suggest via mechanism, specifically by decreasing level COPB2, which has not been extensively studied context therapy warrants further investigation.

Language: Английский

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Enhancing hepatocellular carcinoma therapy with DOX-loaded SiO2 nanoparticles via mTOR-TFEB pathway autophagic flux inhibition

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 19, 2025

Chemotherapeutic drugs often fail to provide long-term efficacy due their lack of specificity and high toxicity. To enhance the biosafety reduce side effects these drugs, various nanocarrier delivery systems have been developed. In this study, we loaded anticancer drug doxorubicin (DOX) an MRI contrast agent into silica nanoparticles, coating them with pH-responsive tumor cell-targeting polymers. These polymers enable carrier achieve targeted controlled release in acidic environments. This integrated diagnostic therapeutic strategy successfully achieved both diagnosis treatment liver cancer. Additionally, demonstrated that inhibits autophagic flux cancer cells by targeting autophagy-lysosome pathway regulating nuclear translocation TFEB, thereby promoting cell death. novel diagnostic-integrated is expected be a promising tool for treatment.

Language: Английский

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Free fatty acids derived from lipophagy enhanced resistance to anoikis by activating Src in high-invasive clear cell renal cell carcinoma cells

Cellular Signalling, Journal Year: 2025, Volume and Issue: unknown, P. 111622 - 111622

Published: Jan. 1, 2025

Language: Английский

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Modulation of Autophagy by Oncosuppressor FAM46C and Its Implications for Cancer Therapy: An Intriguing Perspective

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 196 - 196

Published: Jan. 30, 2025

Cancer is one of the major challenges in medicine, necessitating continuous advancements therapeutic approaches. Autophagy, an intracellular pathway essential for cellular homeostasis and stress response, has emerged as a promising target cancer treatment. In this context, FAM46C, novel pan-cancer tumour suppressor, been shown to induce apoptosis multiple myeloma cells through indirect inhibition autophagy. Here, we discuss how FAM46C-induced autophagic dampening could offer new opportunities global therapy. Specifically, explore two scenarios which expression functional FAM46C may either sensitize or antagonize their sensitivity. We further comment on synergism/antagonism be used refine strategies treatment, positioning pivotal factor future therapy development.

Language: Английский

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The crosstalk between SND1 and PDCD4 is associated with chemoresistance of non-small cell lung carcinoma cells

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 30, 2025

Language: Английский

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Extracellular Vesicle-based Delivery of Paclitaxel to Lung Cancer Cells: Uptake, Anticancer Effects, Autophagy and Mitophagy Pathways

Archives of Medical Research, Journal Year: 2025, Volume and Issue: 56(4), P. 103194 - 103194

Published: Feb. 7, 2025

Language: Английский

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Nanomedicine Approaches for Autophagy Modulation in Cancer Therapy

Small Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Cancer is a daunting global health problem with steadily rising incidence. Despite the wide arsenal of current anticancer therapies, challenges such as drug resistance, tumor heterogeneity, poor targeting, and severe side effects often lead to suboptimal efficacy patient outcomes, highlighting need for innovative therapies. Autophagy modulation has emerged an attractive approach complement existing The dual role autophagy in cancer promotion suppression inspired development new drugs therapeutic strategies focusing on both inhibition induction. promising results modulators preclinical studies, lack selectivity potency, toxicity, pharmacokinetics, inadequate targeting continue limit their successful clinical translation. Many these could be overcome using nanomedicine. This review explores recent advancements nanomedicine modulation. Successful combination leveraging nanoparticles synergy chemotherapy, immunotherapy, phototherapy, gene therapy, other modalities are presented. Additionally, nanomaterials intrinsic autophagy‐modulating capabilities, self‐assembling inhibitors, discussed. Finally, limitations currently trials discussed, future perspectives designing implementation explored.

Language: Английский

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Enhanced cytotoxicity of T-DM1 in HER2-low carcinomas via autophagy inhibition

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(5), P. e0322029 - e0322029

Published: May 2, 2025

Ado-trastuzumab emtansine (T-DM1), a conjugate of trastuzumab and the cytotoxic agent emtansine, has demonstrated significant antitumor efficacy in HER2-positive (HER2+) carcinoma. However, its effectiveness is limited against carcinoma cells with low HER2 expression (HER2-low). Here, we demonstrate that targeting autophagy enhances cytotoxicity T-DM1 HER2-low SGC7901 cells, highlighting potential modulation improving T-DM1-based therapies for carcinomas. Specifically, this study shows exhibits effects on but pharmacological inhibition cytotoxicity. Moreover, transmission electron microscopy revealed activation involved three key phases autophagic flux: formation, fusion, degradation autophagosomes, while immunoblot analysis confirmed reduction Akt/mTOR signaling. Furthermore, accelerated fusion lysosomes as shown by confocal microscopy. Collectively, these findings suggest alone induces cytotoxicity, combining it inhibitors cells. Mechanistically, increases binding to lysosomes, potentially facilitating release from conjugate. These results present novel strategy combines effectively treat gastric cancer, thereby broadening therapeutic scope encompass previously challenging cancer types.

Language: Английский

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Lysionotin promoted apoptosis of hepatocellular carcinoma cells via inducing autophagy

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 2, 2025

Background Hepatocellular carcinoma is a prevalent malignant tumor with high mortality rate. Natural plants hold promise for its treatment, however, the mechanism of lysionotin induced apoptosis in liver cancer cells unclearly. This study aims to investigate microenvironment alterations and efficacy cancer. Methods Transmission electron microscopy, laser confocal microscopy were employed effect on autophagy HCC cells. The molecular through which induces autophagy-induced was ascertained by transcriptome sequencing, immunoblotting Hoechst 33258 staining. Results RNA sequencing analysis, revealed that initiate Immunoblotting indicated markedly enhances activation LC3-II cells, resulting key effector molecules ATG12, Beclin-1 degradation P62. Combined inhibitors CQ 3-MA significantly inhibited lysionotin-induced cell apoptosis. staining disclosed might be associated suppression mTOR-AKT signaling pathway. treatment mTOR inhibitor RAPA activator 1485 demonstrated inhibiting augments pro-apoptotic while could rescue Conclusions findings suggest may represent one pivotal mechanisms underlying therapeutic against synergistic enhancement RAPA's antitumor effects.

Language: Английский

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Isolinderalactone Induces Apoptosis, Autophagy, Cell Cycle Arrest and MAPK Activation through ROS–Mediated Signaling in Colorectal Cancer Cell Lines

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14246 - 14246

Published: Sept. 18, 2023

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Isolinderalactone (ILL), a sesquiterpene isolated from root extract Lindera aggregata, has been reported to exhibit anti-proliferative and anti-metastatic activities in various cell lines. However, mechanisms associated with its antitumor effects on CRC cells remain unclear. ILL treatment significantly suppressed proliferation induced cycle G2/M arrest by inhibiting expression cyclin B, p-cdc2, p-cdc25c up-regulating p21. In addition, mitochondria-associated apoptosis through up-regulation cleaved -caspase-9 -3 expression. autophagy increasing levels LC3B cells, which was partially rescued an inhibitor (chloroquine). Furthermore, increases accumulation reactive oxygen species (ROS) activates MAPK pathway. Application ROS scavenger, N-acetyl cysteine (NAC), effectively inhibited toxicity reversed ILL-induced apoptosis, arrest, autophagy, ERK activation. Taken together, these results suggest that induces phase pathway via ROS-mediated signaling human cells.

Language: Английский

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